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*
Neuroscience Group, Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom;
Ludwig Institute for Cancer Research, and Department of Biochemistry and Molecular Biology, University College, London, United Kingdom; and
Anergen Inc., Redwood City, CA 94063.
A recurring epitope in the human acetylcholine receptor (AChR) 
subunit (146–160) is presented to specific T cells from myasthenia
gravis patients by HLA-DRB3*0101—"DR52a"—or by DR4. Here we first
map residues critical for DR52a in this epitope by serial Ala
substitution. For two somewhat similar T cells, this confirms the
recently deduced importance of hydrophobic "anchor" residues at
peptide p1 and p9; also of Asp at p4, which complements this allele’s
distinctive Arg74 in DRß. Surprisingly, despite the 9
sequence differences in DRß between DR52a and DR3, merely reducing
the bulk of the peptide’s p1 anchor residue (Trp149
Phe)
allowed maximal cross-presentation to both T cells by DR3 (which has
Val86 instead of Gly). The shared
K71G73R74N77 motif in
the helices of DR52a and DR3 thus outweighs the five differences in
the floor of the peptide-binding groove. A second issue is that T cells
selected in vitro with synthetic AChR peptides rarely respond to longer
Ag preparations, whereas those raised with recombinant subunits
consistently recognize epitopes processed naturally even from whole
AChR. Here we compared one T cell of each kind, which both respond to
many overlapping 140–160 region peptides (in proliferation assays).
Even though both use Vß2 to recognize peptides bound to the same
HLA-DR52a in the same register, the peptide-selected line nevertheless
proved to depend on a recurring synthetic artifact—a widely
underestimated problem. Unlike these contaminant-responsive T cells,
those that are truly specific for natural AChR epitopes appear less
heterogeneous and therefore more suitable targets for selective
immunotherapy.
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